This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this renewal application, we request time to continue our investigation of the mechanism of several membrane transporters and channels using simulation methodologies. Several active transporters that use various source of energy in a living cell for their function will be investigated. Furthermore, we will also continue our research on another membrane associated phenomenon, namely mechanism of membrane binding and activation of blood coagulation factors, which constitutes the most productive project over the past funding period, and a strong collaborative effort between 5 labs at UIUC. In fact, all of the projects are conducted in close collaboration with leading experimental groups. All Projects address rather slow processes, thus, requiring long simulations. Furthermore, due to the need of explicit representation of the lipid and water, which play role in the mechanism of transporters, and due to the complexity of the structure, large molecular assemblies need to be simulated. Such calculations can only be carried out with the advanced TeraGrid computational resources. The size and complexity of the function of these proteins pose a great challenge for computational studies. Over the last funding period, however, we have demonstrated through several published papers reported in the Progress Report, that large scale MD simulations can indeed significantly advance our understanding of the molecular mechanisms of energy coupling and transport phenomena in these biomolecules. Due to limited space and the need to describe 6 projects, we have delegated the progress and discussion of our preliminary results completely to the Progress Report. Our extensive use of the allocation over the past funding period is the strongest evidence for the computational demands of such biomolecular systems. We note, however, that we have used the allocated time extremely productively and produced a record number of publications (16;please see Progress Report) over the past funding cycle. We would like to give a general clarification with regard to the length of the proposed simulations, which might be perceived as an "unjustified" aspect. All of the projects address rather slow biomolecular processes (at least on the order of microsecond). As such, even orders of magnitude longer simulations than those described in this application can be easily justified from a technical point of view. However, we realize that such processes (e.g., complete transport cycle) cannot be currently described in their entirety, and we can only expect to cover some of the steps involved in such processes. Therefore, in order to provide a justification that will hopefully be satisfactory, almost in all cases we will base the length of the proposed simulations on our existing benchmarks (mostly published) of the same or comparable systems/phenomena.